The antibacterial compound cephalosporin C was first isolated by Newton and Abraham (Nature, 175:548, 1955). The antibacterial activity of cephalosporin C was generally low, however was still worthy of attention because it proved to be effective against organisms that had developed resistance to penicillins. Cephalosporin C is secreted by cephalosporium acremonium and is commercially produced in a fermentation broth containing cephalosporium acremonium cultures in an aqueous environment.
Cephalosporin C can be synthesized to 7-ACA, an important intermediate in the production of cephalosporin antibiotics such as cephaloridine, cefazolin, cefamandole, cefatrizine and cefazaflur. Conversion of Cephalosporin C to 7-ACA may be carried out by a chemical cleavage process, most generally using organic halides and PCl.sub.5 (Huber, F. M., et al., Cephalosporins and Penicillins, (Academic Press, New York, pp 27-73, (1972)).
It has been reported that glutaryl 7-ACA may be formed by oxidative deamination of the .alpha.-aminoadipoyl side chain of cephalosporin C, either chemically (Matsuda, et al., U.S. Pat. No. 3,960,662) or enzymatically (Fildes, et al., British Patent No. 1,272,769 (1972)). Thereafter, the glutaryl 7-ACA may be converted to 7-ACA by an enzymatic side chain cleavage (Suzuki, et al., U.S. Pat. No. 4,079,180).
The production and isolation of cephalosporin C has been complicated by the presence of desacetyl cephalosporin C in the fermentation broth. In the above described oxidation/7-position side chain cleavage process to obtain 7-ACA from cephalosporin C via glutaryl 7-ACA, it has been determined that not only glutaryl 7-ACA is formed after the first step, but so is desacetyl glutaryl 7-ACA. Up to this time it has been a practice to remove the desacetyl glutaryl 7-ACA. The two step process could afford additional benefits if a substantial amount of desacetyl glutaryl 7-ACA could be utilized.
At the present, acetylation of the 3-hydroxymethyl has not been able to be carried out on unprotected cephalosporins in aqueous solutions. Previous work by Van Heyningen (J. Med. Chem. 8, 22 (1965)) indicated that the 3' acetylation of desacetyl cephalosporins in aqueous media was hindered because of the ease with which the 3-hydroxymethyl lactonized with the 4 carboxyl to form the lactone.
It has been indicated that aromatic acid chlorides may be successfully used to esterify the 3'-hydroxyl of desacetyl cephalosporins. Summerfield, et al., U.S. Pat. No. 3,532,694 were able to acetylate the 3-hydroxymethyl group by first forming an ester at the 4-carboxy position to prevent lactone formation. This reaction was performed in anhydrous solvents using an organic base.
Tsushima, et al. (Japanese laid opened patent application No. 52027792; and Chem. Pharm. Bull. 27, 696 (1979)) were able to acetylate desacetyl cephalosporins in nonaqueous solvents such as dimethyl formamide.
It would be advantageous to provide a process for acetylation of 3-hydroxymethyl cephalosporin under aqueous conditions. The present invention is directed to such a process.